This Physician Scientist Award is designed to enable the applicant to develop the skills and perspective of a competent research scientist through intensive training and experience in basic musculoskeletal research. The applicant will specifically focus on physiologic mechanisms regulating the biologic response of trabecular bone to mechanical stimuli. The response of bone to mechanical stimuli, generally known as Wolff's law is widely accepted. While studies investigating the structural adaptation of bone to physical forces are underway, the cellular and molecular mechanisms regulating this adaptive response remain unclear. A unique large volume, bone chamber equipped with a hydraulic actuator, provides the appropriate in vivo microenvironment in which to investigate these relationships. A variety of cytokines, transmembrane proteins, second messengers and even osteoblasts themselves have been proposed, as a result of in vitro studies, to mediate the transduction of a mechanical stimulus into biologic activity. Utilizing immunolocalization and in situ hybridization techniques these agents may be identified within specific cell populations in a sample of bone chamber tissue subjected to a controlled loading regimen. This is the aim of the second phase of this proposal which will be accomplished utilizing the technical skills and knowledge gained during Phase l. Increasing our understanding of the complex interactions between physical forces and the cellular microenvironment of trabecular bone will provide insight into normal bone physiology and potential treatment modalities for conditions of bone fragility.